US20170071976A1 - Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same - Google Patents

Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same Download PDF

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US20170071976A1
US20170071976A1 US15/360,065 US201615360065A US2017071976A1 US 20170071976 A1 US20170071976 A1 US 20170071976A1 US 201615360065 A US201615360065 A US 201615360065A US 2017071976 A1 US2017071976 A1 US 2017071976A1
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solution
deuterium oxide
tumor
cancer
sodium chloride
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Songyuan Chen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure belongs in the field of medicine, and relates to a pharmaceutical solution having an anti-tumor efficacy-enhancing and toxicity-reducing effect, and a pharmaceutical composition comprising the solution, as well as a method for using them.
  • the main therapies against malignant tumors are surgery, radiotherapy, and chemotherapy with various anti-tumor drugs, and these methods have their own characteristics but also certain limitations, especially the unremarkable efficacy often shown in chemotherapy with anti-tumor drugs.
  • a commonly used anti-tumor drug 5-fluorouracil (5-FU) shows an overall response rate of only 10% as a single drug in clinical settings.
  • many anti-tumor drugs have considerable toxicity which is proportional to their dose.
  • an increase in dosage of a drug is needed but also results in an increase in toxicity caused by the drug, which poses a dilemma. Therefore, to increase the efficacy of anti-tumor drugs while reducing their toxicity is an important strategy towards improvement of clinical efficacy of anti-tumor drugs.
  • anti-tumor drugs must be systemically or topically administered by injection because of their physical or chemical properties, pharmacokinetics and pharmacodynamics. These are commonly used as carrier solutions such as a sodium chloride physiological solution and a 5% glucose solution. These solutions only serve as carriers for anti-tumor drugs, and they neither have any anti-tumor efficacy nor can enhance the efficacy of the anti-tumor drugs.
  • Deuterium oxide (heavy water, D 2 O, Mw: 20.03, CAS No. 7789-20-0) can be isolated from seawater.
  • a normal body of adult human contains about 5 g deuterium oxide. It has been demonstrated by experiments using dogs as an animal model that exogenous deuterium oxide that reaches a concentration of 30% in the body causes a toxic effect. Based on this experimental result, theoretically, assuming the body weight of an adult human is 60 kg, deuterium oxide that reaches 18 kg in the body starts to cause toxicity. However, it is actually impossible for a human body to have 18 kg deuterium oxide. Furthermore, the state government of California, USA clearly indicates in the list of chemicals known to the State that deuterium oxide does not cause cancer or defect in reproductive development.
  • deuterium oxide should be a non-toxic substance [D. M. Czajka: Am. J. Physiol. 201(1961): 357-362; California Proposition 65].
  • Gross P. R. et al. found that deuterium oxide may inhibit DNA synthase in cells ( Science 133(1961): 1131-1133).
  • Laissue et al. studied the anti-tumor effect of deuterium oxide using mice as a model ( Cancer Res. 42 (1982) 1125-1129), and Alterman et al. studied the anti-tumor effect of drinking deuterium oxide in animals using nude mice bearing a human tumor cells as a model ( Cancer 62(1988): 462-466. Intl. Cancer.
  • the animals need to orally take a large dose of the drinking liquid of deuterium oxide.
  • a drinking liquid of deuterium oxide at a concentration of 30% was prepared by mixing deuterium oxide with drinking water, and used to completely replace drinking water for the animals to drink freely and arbitrarily.
  • the animals reached a deuteration state with a very high level of deuterium, which starts to exert an anti-tumor effect.
  • hyperthermic perfusion and lavage 2) direct injection of small doses of deuterium oxide changes the cell cycle of tumor cells and kills tumor cells; 3) efficacy-enhancing and toxicity reducing effect is obtained by directly dissolving or diluting a small dose of anti-tumors drugs in deuterium oxide, and administering the solution by injection, or by topical (such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, rectal lumen, buccal and nasal cavity, uterine cavity, articular cavity, and skin) perfusion and lavage and 40° C.-48° C.
  • topical such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, rectal lumen, buccal and nasal cavity, uterine cavity, articular cavity, and skin
  • hyperthermic perfusion and lavage which can achieve the same efficacy as a large dose of the anti-tumor drugs but avoid the toxicity therefore; the application of deuterium oxide with hyperthermia exhibiting an unexpected anti-tumor effect of enhancing, thereby also improves quality of life of the mammal having a tumor; 4) drug approvability is increased: administration of deuterium oxide by injection allows dosage quantification, which overcomes the drawback of short of drug approvability due to arbitrary drinking without a quantified dose; 5) safety is achieved: administration of a certain dose of deuterium oxide by direct injection, or by topical (such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, rectal lumen, buccal and nasal cavity, uterine cavity, articular cavity, and skin) perfusion and lavage and 40° C.-48° C. hyperthermic perfusion and lavage is safe to mammals.
  • topical such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, rectal lume
  • deuterium oxide per se has anti-tumor efficacy, and when administered in combination with various different anti-tumor drugs, it can significantly enhance the anti-tumor efficacy in a synergistic manner and also reduce toxicity of these anti-tumor drugs, thereby useful for treatment of malignant tumors, which is an unexpected effect.
  • An aspect of the present disclosure is to provide a pharmaceutical solution characterized by using deuterium oxide as a solvent.
  • Another aspect of the present disclosure is to provide a medicament for combinational administration, characterized in that the medicament comprises the pharmaceutical solution of the present disclosure, at least one anti-tumor drug, and optionally one or more pharmaceutically acceptable excipients.
  • Another aspect of the present disclosure is to provide a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the pharmaceutical solution of the present disclosure, at least one anti-tumor drug, and optionally one or more pharmaceutically acceptable excipients.
  • Another aspect of the present disclosure is to provide use of the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure in the manufacture of an anti-tumor agent.
  • Another aspect of the present disclosure is to provide a method for preventing or treating tumors, comprising administering a therapeutically effective amount of the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure, to a mammal having a tumor.
  • Another aspect of the present disclosure is to provide a method for preventing or treating tumors, characterized in that the medicament for combinational administration comprises deuterium oxide and at least one anti-tumor drug, wherein the deuterium oxide and the anti-tumor drug may be administered separately or concomitantly.
  • Another aspect of the present disclosure is to provide a method for preventing or treating tumors, wherein the pharmaceutical solution, the medicament for combinational administration, and the pharmaceutical composition are a solution for lavage and perfusion, a solution for injection, a suspension, an emulsion, or an embolization.
  • Another aspect of the present disclosure is to provide a method for preventing or treating tumors, comprising administering a therapeutically effective amount of the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure to a mammal having a tumor by various administration routes, excluding oral administration, including intravenous injection or instillation, intra-arterial injection, topical perfusion and lavage, topical hyperthermic perfusion and lavage, trascatheter embolization, topical intratumoral and peritumoral administration.
  • oral administration including intravenous injection or instillation, intra-arterial injection, topical perfusion and lavage, topical hyperthermic perfusion and lavage, trascatheter embolization, topical intratumoral and peritumoral administration.
  • Another aspect of the present disclosure is to provide a method for preventing or treating malignant tumors, wherein administration by perfusion and lavage is performed by perfusing and lavaging topical sites of the mammal having a tumor, such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, buccal cavity, nasal cavity, enteric cavity, uterine cavity, articular cavity, and skin, with a solution for perfusion and lavage.
  • a tumor such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, buccal cavity, nasal cavity, enteric cavity, uterine cavity, articular cavity, and skin
  • Another aspect of the present disclosure is to provide a method for preventing or treating malignant tumors, wherein in administration by hyperthermic perfusion and lavage, the temperature of the solution for perfusion and lavage is 40° C. to 48° C., preferably 42° C. to 44.5° C., and more preferably 42° C.
  • Another aspect of the present disclosure is to provide a method for preventing or treating malignant tumors, wherein in administration by perfusion and lavage or by hyperthermic perfusion and lavage, the dose of the solution for perfusion and lavage are 5 to 6,000 ml/administration to the mammal having a tumor.
  • Another aspect of the present disclosure is to provide a method for preventing or treating malignant tumors, wherein in administration by intravenous injection, intra-arterial injection, intrathecal injection, or intratumoral and peritumoral injection, the dose of the solution for injection is 1 ml/kg to 20 ml/kg to the mammal having a tumor.
  • the mammal is selected from a rodent and a human.
  • Another aspect of the present disclosure is to provide use of deuterium oxide in the manufacture of a pharmaceutical solution.
  • the pharmaceutical composition or the medicament for combinational administration according to the present disclosure shows a marked anti-tumor effect and lower toxicity than current anti-tumor drugs.
  • the pharmaceutical composition or the medicament for combinational administration according to the present disclosure is useful for treatment or prevention of malignant tumors.
  • Deuterium oxide shows an effect of synergistically enhancing the anti-tumor efficacy of anti-tumor drugs, such that a small dose of anti-tumor drugs can achieve the same efficacy as a large dose of the anti-tumor drugs, thereby reducing the amount and toxicity of anti-tumor drugs to be used.
  • the pharmaceutical composition or the medicament for combinational administration according to the present disclosure is useful for preventing or reducing invasion, metastasis, recurrence, and drug-resistance of tumors.
  • FIG. 1 Effect of deuterium oxide on the cell cycle of human colon cancer HCT-166 cells.
  • FIG. 2 Effect of deuterium oxide on the cell cycle of human colon cancer HCT-166 cells, as measured by the FCM method.
  • FIG. 3 Effect of deuterium oxide on the cell cycle of human lung cancer A549 cells.
  • FIG. 4 Effect of deuterium oxide on the cell cycle of human lung cancer A549 cells, as measured by the FCM method.
  • FIG. 5 Effect of the glucose deuterium oxide solution in combination with 5-FU on the tumor size of xenograft tumors from human colon cancer HCT-166 cells in nude mice.
  • FIG. 6 Effect of the glucose deuterium oxide solution in combination with 5-FU on the tumor weight of xenograft tumors from human colon cancer HCT-166 cells in nude mice.
  • FIG. 7 Effect of the glucose deuterium oxide solution in combination with 5-FU on the body weight of nude mice bearing xenograft tumors from human colon cancer HCT-166 cells.
  • FIG. 8 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the tumor size of xenograft tumors from human breast cancer MCF-7 cells in nude mice.
  • FIG. 9 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the tumor weight of xenograft tumors from human breast cancer MCF-7 cells in nude mice.
  • FIG. 10 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the body weight of nude mice bearing xenograft tumors from human breast cancer MCF-7 cells.
  • FIG. 11 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the tumor size of xenograft tumors from human lung cancer A549 cells in nude mice.
  • FIG. 12 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the tumor weight of xenograft tumors from human lung cancer A549 cells in nude mice.
  • FIG. 13 Effect of the sodium chloride deuterium oxide solution in combination with Gemcitabine on the body weight of nude mice bearing xenograft tumors from human lung cancer A549 cells.
  • DJ and HW refer to deuterium oxide.
  • the present application relates to the following embodiments.
  • a pharmaceutical solution characterized by using deuterium oxide as a solvent.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution comprises sodium chloride and deuterium oxide, being a sodium chloride deuterium oxide solution containing 0.1 g to 5 g sodium chloride, preferably 0.5 g to 2.5 g sodium chloride per 100 ml solution.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution comprises sodium chloride and deuterium oxide, being a sodium chloride deuterium oxide solution containing 0.9 g sodium chloride per 100 ml solution, which is prepared with deuterium oxide and sodium chloride and has a pH of 4.5 to 7.0.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution comprises glucose and deuterium oxide, being a glucose deuterium oxide solution containing 0.1 g to 50 g glucose, preferably 5 to 10 g, most preferably 5 g glucose per 100 ml pharmaceutical solution, which is prepared with deuterium oxide and glucose and has a pH of 3.2 to 6.5.
  • the pharmaceutical solution comprises glucose and deuterium oxide, being a glucose deuterium oxide solution containing 0.1 g to 50 g glucose, preferably 5 to 10 g, most preferably 5 g glucose per 100 ml pharmaceutical solution, which is prepared with deuterium oxide and glucose and has a pH of 3.2 to 6.5.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution comprises glucose and sodium chloride and deuterium oxide, being a glucose sodium deuterium oxide solution containing 0.9 g sodium chloride and 5 g glucose per 100 ml pharmaceutical solution, which is prepared with deuterium oxide, sodium chloride and glucose and has a pH of 3.5 to 5.5.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution comprises sodium bicarbonate and deuterium oxide, being a sodium bicarbonate deuterium oxide solution containing 1 to 10 g, preferably 5 to 10 g, most preferably 5 g sodium bicarbonate per 100 ml pharmaceutical solution, which is prepared with deuterium oxide and sodium bicarbonate and has a pH of 7.5 to 8.5.
  • the pharmaceutical solution according to Embodiment 1 characterized in that, the pharmaceutical solution is a Ringer's deuterium oxide solution containing 0.85 g sodium chloride, 0.012 g potassium chloride and 0.024 g calcium chloride (CaCl 2 .2H 2 O) per 100 ml pharmaceutical solution, which is prepared with deuterium oxide, sodium chloride, potassium chloride and calcium chloride and has a pH of 4.5 to 7.5.
  • the pharmaceutical solution is a Ringer's deuterium oxide solution containing 0.85 g sodium chloride, 0.012 g potassium chloride and 0.024 g calcium chloride (CaCl 2 .2H 2 O) per 100 ml pharmaceutical solution, which is prepared with deuterium oxide, sodium chloride, potassium chloride and calcium chloride and has a pH of 4.5 to 7.5.
  • the pharmaceutical solution comprises sodium hyaluronate and deuterium oxide, being a sodium hyaluronate deuterium oxide solution containing 0.04 to 3 g, preferably 0.08 to 1.4 g sodium hyaluronate, most preferably being a sodium hyaluronate deuterium oxide solution containing 0.08 or 1.0 g sodium hyaluronate, 0.9 g sodium chloride, 0.142 g disodium hydrogen phosphate and 0.027 g sodium dihydrogen phosphate per 100 ml pharmaceutical solution and having a pH adjusted to 6.5 to 7.5.
  • sodium hyaluronate and deuterium oxide being a sodium hyaluronate deuterium oxide solution containing 0.04 to 3 g, preferably 0.08 to 1.4 g sodium hyaluronate, most preferably being a sodium hyaluronate deuterium oxide solution containing 0.08 or 1.0 g sodium hyaluronate, 0.9 g sodium chloride, 0.
  • the pharmaceutical solution comprises hydroxyethyl starch and deuterium oxide, being a hydroxyethyl starch deuterium oxide solution containing 3 to 8 g hydroxyethyl starch, most preferably being a solution of hydroxyethyl starch and sodium chloride in deuterium oxide containing 6 g hydroxyethyl starch and 0.9 g sodium chloride per 100 ml pharmaceutical solution and having a pH adjusted to 6.0 to 7.0.
  • hydroxyethyl starch and deuterium oxide being a hydroxyethyl starch deuterium oxide solution containing 3 to 8 g hydroxyethyl starch, most preferably being a solution of hydroxyethyl starch and sodium chloride in deuterium oxide containing 6 g hydroxyethyl starch and 0.9 g sodium chloride per 100 ml pharmaceutical solution and having a pH adjusted to 6.0 to 7.0.
  • the pharmaceutical solution comprises hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and deuterium oxide, being a HP- ⁇ -CD deuterium oxide solution containing 0.4 to 10 g HP- ⁇ -CD, most preferably being a HP- ⁇ -CD sodium chloride deuterium oxide solution containing 10 g HP- ⁇ -CD and 0.9 g sodium chloride per 100 ml pharmaceutical solution and having a pH adjusted to 5.0 to 7.0.
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • deuterium oxide being a HP- ⁇ -CD deuterium oxide solution containing 0.4 to 10 g HP- ⁇ -CD, most preferably being a HP- ⁇ -CD sodium chloride deuterium oxide solution containing 10 g HP- ⁇ -CD and 0.9 g sodium chloride per 100 ml pharmaceutical solution and having a pH adjusted to 5.0 to 7.0.
  • the pharmaceutical solution according to Embodiments 1 to 10 characterized in that, the pharmaceutical solution is a solution for lavage and perfusion, a solution for injection, a suspension, an emulsion, or a solution for embolization.
  • An anti-tumor medicament for combinational administration characterized in that the medicament comprises the pharmaceutical solution according to any one of Embodiments 1 to 10, at least one anti-tumor drug, and optionally one or more pharmaceutically acceptable excipients.
  • the tumor antibiotics include mitomycin, epirubicin, peplomycin, daunorubicin, adriamycin, pirarubicin, aclarubicin;
  • the platinum preparations include cisplatin, oxaliplatin, carboplatin, nedaplatin;
  • the phytogenic anti-tumor drugs include paclitaxel, paclitaxel liposomes, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin;
  • the alkylating agents include thiotepa, carmustine, nimustine, fotemustine, estramustine, cyclophosphamide, myleran.
  • An anti-tumor pharmaceutical composition characterized in that the pharmaceutical composition comprises the pharmaceutical solution according to any one of Embodiments 1 to 11, at least one anti-tumor drug, and optionally one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition according to Embodiment 18, wherein the anti-tumor cytotoxic drugs include antimetabolites, phytogenic anti-tumor drugs, tumor antibiotics, alkylating agents, monoclonal antibodies, and platinum preparations.
  • the tumor antibiotics include mitomycin, epirubicin, peplomycin, daunorubicin, adriamycin, pirarubicin, aclarubicin;
  • the platinum preparations include cisplatin, oxaliplatin, carboplatin, nedaplatin;
  • the phytogenic anti-tumor drugs include paclitaxel, paclitaxel liposomes, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin;
  • the alkylating agents include thiotepa, carmustine, nimustine, fotemustine, estramustine, cyclophosphamide, myleran.
  • the pharmaceutical composition according to Embodiment 20, wherein the monoclonal antibody anti-tumor drugs include bevacizumab, cetuximab, trastuzumab, panitumumab, nimotuzumab, recombinant human endostatin.
  • a method for treating or preventing tumors comprising administering a therapeutically effective amount of the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure to a mammal having a tumor by various administration routes, excluding oral administration, including intravenous injection or instillation, intra-arterial injection, topical perfusion and lavage, topical hyperthermic perfusion and lavage, transcatheter embolization, topical intrathecal injection, and intratumoral and peritumoral injection.
  • oral administration including intravenous injection or instillation, intra-arterial injection, topical perfusion and lavage, topical hyperthermic perfusion and lavage, transcatheter embolization, topical intrathecal injection, and intratumoral and peritumoral injection.
  • the temperature of the solution for lavage and perfusion is 40° C. to 48 ⁇ 1° C., preferably 42° C. to 44.5 ⁇ 1° C., and more preferably 42 ⁇ 1° C.
  • the administration by topical perfusion and lavage or by topical hyperthermic perfusion and lavage is performed by perfusing and lavaging topical sites, such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, buccal cavity, nasal cavity, enteric cavity, uterine cavity, articular cavity, and skin, of the mammal with a solution for lavage and perfusion in a dose of 5 to 6,000 ml/administration.
  • topical sites such as thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, buccal cavity, nasal cavity, enteric cavity, uterine cavity, articular cavity, and skin
  • the dose of the solution for injection is 1 ml/kg to 20 ml/kg.
  • a method for treating or preventing tumors comprising administering a therapeutically effective amount of the pharmaceutical solution according to any one of Embodiments 1 to 12, the medicament for combinational administration according to any one of Embodiments 13 to 17, or the pharmaceutical composition according to any one of Embodiments 18 to 22 to a mammal having a tumor.
  • Embodiment 29 wherein the pharmaceutical solution serves as a broad-spectrum anti-tumor efficacy-enhancing agent, and synergistically enhances the efficacy of anti-tumor drugs.
  • every 100 ml of the pharmaceutical solution or pharmaceutical composition contains 1 to 99.9 g deuterium oxide, preferably 9 to 99.9 g deuterium oxide, more preferably 20 to 99.9 g deuterium oxide, even more preferably 30 to 99.9 g deuterium oxide, even more preferably 40 to 99.9 g deuterium oxide, even more preferably 50 to 99.9 g deuterium oxide, even more preferably 60 to 99.9 g deuterium oxide, even more preferably 70 to 99.9 g deuterium oxide, even more preferably 80 to 99.9 g deuterium oxide, even more preferably 90 to 99.9 g deuterium oxide, and most preferably 95 to 99.9 g deuterium oxide.
  • Deuterium oxide according to the present disclosure is produced by deuterium oxide plants, and is commercially available.
  • the isotope abundance of deuterium is 1 to 99.9%, preferably 30 to 99.9%, more preferably 50 to 99.9%, more preferably 70 to 99.9%, and most preferably 90 to 99.9%.
  • the deuterium oxide provided by Cambridge Isotope Laboratories, Inc. USA, may be used, which has an isotope abundance of deuterium of 90 to 99.9% (D 90-99.9%).
  • the pharmaceutically excipients may be water, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, sodium citrate, sodium bicarbonate, potassium dihydrogen phosphate, disodium hydrogenphosphate, sodium bicarbonate, glucose, fructose, albumin, liposomes, hyaluronic acid, and/or polyethylene glycol.
  • the anti-tumor drug is selected from anti-tumor cytotoxic drugs and monoclonal antibody anti-tumor drugs.
  • the anti-tumor cytotoxic drugs include antimetabolites, phytogenic anti-tumor drugs, tumor antibiotics, alkylating agents, monoclonal antibodies, and platinum preparations.
  • the antimetabolites include 5-fluorouracil, gemcitabine, floxuridine, pemetrexed, raltitrexed, fludarabine, cytarabine; preferably 5-fluorouracil, gemcitabine, and pemetrexed.
  • the tumor antibiotics include mitomycin, epirubicin, peplomycin, daunorubicin, adriamycin, pirarubicin, aclarubicin; preferably mitomycin and epirubicin.
  • the platinum preparations include cisplatin, oxaliplatin, carboplatin, nedaplatin; preferably cisplatin and oxaliplatin.
  • the phytogenic anti-tumor drugs include paclitaxel, paclitaxel liposomes, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin; preferably paclitaxel, paclitaxel liposomes, paclitaxel albumin, and docetaxel.
  • the alkylating agents include thiotepa, carmustine, nimustine, fotemustine, estramustine, cyclophosphamide, myleran; preferably thiotepa and carmustine.
  • the monoclonal antibody anti-tumor drugs include bevacizumab, cetuximab, trastuzumab, panitumumab, nimotuzumab, recombinant human endostatin; preferably bevacizumab and recombinant human endostatin.
  • the pharmaceutical solution according to the present disclosure is prepared by standard methods for preparing solution in the field of pharmaceutics, and satisfies relevant standards in Chinese Pharmacopoeia, United States Pharmacopoeia , and European Pharmacopoeia.
  • the dissolution or dilution ratios of anti-tumor drugs in the pharmaceutical solution prescribed in Chinese Pharmacopoeia, United States Pharmacopoeia , and European Pharmacopoeia are used.
  • the medicament for combinational administration according to the present disclosure refers to combined administration of one pharmaceutical solution according to the present disclosure and one or more anti-tumor drugs.
  • the pharmaceutical composition according to the present disclosure is a composite formulation prepared from a pharmaceutical solution and one or more anti-tumor drugs.
  • the components in the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure may be administered separately or concomitantly.
  • the pharmaceutical solution, the pharmaceutical composition, or the medicament for combinational administration according to the present disclosure is various preparations such as a solution for perfusion and lavage, a solution for injection, a suspension, an emulsion, or a solution for embolization.
  • the tumor according to the present disclosure is selected from lung cancer, colorectal cancer, primary liver cancer, esophageal cancer, gastric cancer and cardiac cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, head and neck cancer, nasopharyngeal cancer, cervical cancer, ovarian cancer, breast cancer, brain tumor, bone and joint sarcoma, thyroid cancer, skin cancer, malignant melanoma, malignant lymphoma, leukemia, and complications and recurrence of various malignant tumors, such as thoracic, peritoneal and/or pelvic cavity metastasis and implantation of tumor cells, and malignant effusion in thoracic, peritoneal and/or pelvic cavity.
  • Lung cancer includes small cell lung cancer (SCLC), non-small cell lung cancer and the like; colorectal cancer includes early stage colorectal cancer, advanced stage colorectal cancer, and the like; primary liver cancer include the hepatic cell type, hepatic duct cell type, a mixed type, and the like; esophageal cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, and the like; gastric cancer and cardiac cancer include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, malignant gastrointestinal stromal tumor, and the like; pancreatic cancer includes ductal cell carcinoma, osteoclast-like giant cell carcinoma, and the like; renal cell carcinoma includes clear cell carcinoma and papillary renal cell carcinoma; bladder cancer includes urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, and the like; prostate cancer includes adenocarcinoma,
  • the mammal is selected from a rodent and a human.
  • 0.9 g sodium chloride was weighed out, to which 99 g deuterium oxide (D, 99.8%, from Cambridge Isotope Laboratories, Inc., USA, the same below) was added to dissolve the sodium chloride under stirring. Drops of a sodium hydroxide solution were added to adjust the solution pH to 7.0, and then deuterium oxide was added to a final volume of 100 ml. The solution was sterilized by filtration through a 0.2 ⁇ m millipore filter and sealed in a container, to obtain a sodium chloride deuterium oxide solution containing 0.9 g sodium chloride per 100 ml pharmaceutical solution according to the present disclosure.
  • deuterium oxide D, 99.8%, from Cambridge Isotope Laboratories, Inc., USA, the same below
  • a method for preparing a warm (40° C. to 48° C.) 0.08% sodium hyaluronate deuterium oxide solution Sodium hyaluronate, (HA, CAS: 9067-32-7, Formula: (C 14 H 2 O 11 N) n , Mw: 10 5 to 10 7 ).
  • the solution comprising 0.08 g sodium hyaluronate, 0.8 g sodium chloride, 0.142 g disodium hydrogen phosphate (Na 2 HPO 4 .12H 2 O) and 0.027 g sodium dihydrogen phosphate (NaH 2 PO 4 ) per 100 ml solution, and having a pH of 6.5 to 7.5.
  • a method for preparing a 1.0% sodium hyaluronate deuterium oxide solution comprising 10 g sodium hyaluronate, 8 g sodium chloride, 1.42 g disodium hydrogen phosphate (Na 2 HPO 4 .12H 2 O) and 0.27 g sodium dihydrogen phosphate (NaH 2 PO 4 ) per 1000 ml solution, and having a pH of 6.5 to 7.5.
  • Hydroxyethyl Starch (CAS: 9005-27-0, Mw: 580.5. Formula: C 22 H 44 O 17 ).
  • hydroxyethyl starch (200/0.5) was weighed out, dissolved in 500 g deuterium oxide to make a solution; 9 g sodium chloride was dissolved in another 500 g deuterium oxide, then the solution of hydroxyethyl starch (200/0.5) deuterium oxide and the solution of sodium chloride deuterium oxide were mixed in a ratio of 1:1, the volume was metered to 1000 ml with deuterium oxide, the pH was adjusted to 6.0 to 7.0, and the solution was sterilized by 0.2 ⁇ m millipore filtration and sealed in a container and was ready for use.
  • a method for preparing a hydroxypropyl- ⁇ -cyclodextrin deuterium oxide solution Hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD, CAS: 128446-35-5. Mw: 1431-1806.
  • Formula: (C 42 H 70 O 35 )-Hn+(C 3 H 7 O 2 ) n ) comprising HP- ⁇ -CD as a solute and deuterium oxide as a solvent, wherein the concentration of HP- ⁇ -CD in the solution is 0.4 to 10 wt %, preferably 10 wt %.
  • 10 g HP- ⁇ -CD was weighed out and dissolved in 100 g deuterium oxide under stirring. The solution contained 10 g HP- ⁇ -CD per 100 ml pharmaceutical solution, the pH was adjusted to 5.0 to 7.0, and the solution was sterilized by 0.2 ⁇ m millipore filtration and sealed in a container and was ready for use.
  • Sulfobutylether- ⁇ -cyclodextrin Sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD. CAS: 25167-62-8) comprising SBE- ⁇ -CD as a solute and deuterium oxide as a solvent, wherein the concentration of SBE- ⁇ -CD in the solution is 3 to 30 wt %, preferably 10 wt %. Most preferably, the solution contained 10 g SBE- ⁇ -CD per 100 ml pharmaceutical solution.
  • the method for warming the solution to a temperature of 40° C. to 48° C. for a solution of or less than 50 ml, the container containing the solution to be used was placed on a small heater or in a water bath at the corresponding temperature for 10 to 20 min; for a solution more than 50 ml, the solution was heated to a temperature of 40° C. to 48° C. in a hyperthermic perfusion and lavage apparatus (BR-TRG-1 hyperthermic perfusion intraperitoneal treatment system, manufactured by Baorui Medical Technology Co., Ltd, Guangzhou, China) and was ready for use.
  • a hyperthermic perfusion and lavage apparatus BR-TRG-1 hyperthermic perfusion intraperitoneal treatment system, manufactured by Baorui Medical Technology Co., Ltd, Guangzhou, China
  • Cell line all cell lines of various types shown in Table 1 were provided by NANJING KEYGEN BIOTECH. CO., LTD and from ATCC, and were commercially available (the same below).
  • Powdery RPMI Medium 1640 (Gibco, USA, Cat#: 31800-022) was dissolved in deuterium oxide (provided by Cambridge Isotope Laboratories, Inc. (US)) to prepare a cell culture medium (unless particularly specified, all culture media used in the Examples hereinafter were prepared from powdery RPMI Medium 1640 and deuterium oxide) at a concentration shown in Table 1, which was added into the cell culture plate. 6. The cell culture plate was incubated for 3 days in an incubator at 37° C., 5% CO 2 and 100% humidity. 7. A solution of 1 mg/ml MTT was prepared in a serum-free RPMI1640 medium, added to the plate at 200 ⁇ l/well, and incubated at 37° C.
  • Table 1 (b) shows IC 50 and IC 10 (expressed in v/v %) of deuterium oxide against different types tumor cells.
  • deuterium oxide shows different IC 50 and IC 10 against different types of tumor cells.
  • deuterium oxide shows a certain inhibitory effect on the growth of various cancer cell lines, and higher contents of deuterium oxide show more significant inhibition of growth of tumor cells.
  • Test drugs 5-fluorouracil (5-FU), and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • 5-fluorouracil was diluted with the sodium chloride deuterium oxide solution according to the concentrations shown in Table 2 and added to a cell culture plate; the in vitro inhibition of tumor cell growth was measured by the MTT assay in the same manner as Example 14.
  • the assay was repeated one more time.
  • deuterium oxide has a sensitizing effect against drug resistance.
  • Test drugs gemcitabine (GEM), 5-fluorouracil (5-FU), and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • Test drugs were added according to different cell treatment groups: gemcitabine or 5-FU diluted in sodium chloride physiological solution only, or gemcitabine or 5-FU diluted in the sodium chloride deuterium oxide solution according to the concentrations shown in Table 3 (i.e. gemcitabine+deuterium oxide, or 5-FU+deuterium oxide), was separately used to treat A549 and HCT116 cells, and the cells were incubated for 24 hours in an incubator at 37° C., 5% CO 2 ; 2. After incubation of cells with the test drugs for 24 hours, serum was removed, and the cells were incubated under starvation with an incomplete culture medium for 24 hours; 3. Matrigel was placed at 4° C. in advance to thaw overnight; 4.
  • Cell counting cells in the Matrigel and the upper compartment were wiped off with a cotton swab, the Transwell was removed, followed by inversion and air drying, 500 ⁇ l medium containing 0.1% crystal violet was added to the 24-well plate, the small compartment was placed in the medium to allow the membrane to be immersed in the dye, removed after holding at 37° C. for 30 min, washed with PBS, and photographed in 3 fields along the diameter (200 ⁇ magnification) for cell counting. 8. The assay was repeated one more time.
  • Deuterium oxide (1.8%) means that the concentration of deuterium oxide in the cell culture medium is 1.8% (v/v), and the same applies hereinafter.
  • 5-FU (0.195 ⁇ g/ml) means that the concentration of 5-FU is 0.195 ⁇ g/ml in sodium chloride physiological solution as the medium.
  • Deuterium oxide (30%)+5-FU (0.195 ⁇ g/ml) means that in the cell culture medium the concentration of deuterium oxide is 30% (v/v), and the concentration of 5-FU is 0.195 ⁇ g/ml.
  • deuterium oxide shows an inhibitory effect on metastasis of various tumor cells, proportional to its dose, and can be combined with other drugs to inhibit metastasis of tumor cells.
  • Human lung cancer A549 cells and human colon cancer HCT-116 cells were provided by NANJING KEYGEN BIOTECH. CO., LTD., and cultured in an incubator at 37° C., 5% CO 2 and saturated humidity.
  • a KGA511 Cell cycle assay kit was provided by NANJING KEYGEN BIOTECH. CO., LTD.
  • the flow cytometer was FACS Calibur provided by Becton-Dickinson, US.
  • Test drugs gemcitabine (GEM), 5-fluorouracil (5-FU), and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • the original culture medium was removed by pipetting when the cell coverage reached 80% to 90% in the culture bottle; 2.2. A suitable amount of trypsin (0.25%) was added to digest for 1 to 2 min; 2.3. When all the cells became round, an equal volume of culture medium containing serum was added to cease the digestion; 2.4. The cells were blown by pipetting to suspend, then drawn into a 15 ml centrifugal tube, and centrifuged at 1000 rpm for 5 min; 2.5. The supernatant was discarded, and the cells were re-suspended in 1 to 2 ml culture medium and transferred to a culture bottle for further culturing.
  • the prepared suspension of individual cells was fixed with 70% (v/v) ethanol for 2 hours (or overnight), and stored at 4° C.; before staining, the fixing solution was washed away with PBS (if necessary, the cell suspension was filtered once through a 200-mesh screen); 5. 100 ⁇ l RNase A was added, and the cells were water-bathed at 37° C. for 30 min; 6. 400 ⁇ l PI was added and well mixed for staining, and the cells were kept at 4° C. in darkness for 30 min; 7. In a detection apparatus, red fluorescence with an excitation wavelength of 488 nm was recorded.
  • 5-FU and gemcitabine are cytotoxic metabolite anti-tumor drugs, and mainly act on tumor cells in the DNA synthesis phase, i.e. the S phase. It can be seen in the results of Tables 8 and 9 and FIGS. 1-4 that deuterium oxide impeded tumor cells entering the G2 phase from the S phase; when deuterium oxide was combined with 5-FU and gemcitabine, 5-FU and gemcitabine kill the S-phase tumor cells more effectively, resulting in significant reduction in the S-phase tumor cells, and exerting a synergistic effect.
  • Test drugs 5-fluorouracil (5-FU), and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • NS sodium chloride physiological solution (same below).
  • Sodium chloride deuterium oxide solution 0.1 ml/animal+5-FU 20 mg/kg means that each mouse was given 0.1 ml sodium chloride deuterium oxide solution, in which 5-FU had been dissolved to make a dose of 20 mg/kg.
  • ascitic fluid was taken from 3 mice from each group, the volume of the ascitic fluid was measured, the number of tumor cells in the ascitic fluid was counted, and the rest of animals were continuously fed. Median survival time (MST) was recorded for animals in each group to evaluate the survival time for each group.
  • MST Median survival time
  • T MST MST of the treatment group
  • C MST MST of the negative control group.
  • the evaluation criterion uses 125% as a cut-off threshold. When T/C % ⁇ 125%, effective, otherwise ineffective.
  • Intraperitoneal lavage with the sodium chloride deuterium oxide solution first, followed by intraperitoneal administration of drugs can achieve a significantly extended MST in mice, longer than the MST resulting from only intraperitoneal administration of drugs in the sodium chloride deuterium oxide solution, namely 29.1 ⁇ 3.1 days vs. 24.1 ⁇ 2.7 days; and 34.5 ⁇ 3.3 days vs. 25.7 ⁇ 2.6 days, both having a P value ⁇ 0.05, demonstrating an advantage of intraperitoneal lavage with deuterium oxide followed by administration of drugs.
  • Modeling human colon cancer HCT-116 cells was taken and adjusted to 1 ⁇ 107 cells/ml, which was inoculated into the peritoneal cavity of mice at 0.1 ml/mouse. 2. Grouping and dosing: the animals were randomized 3 days after inoculation, and meanwhile agents were given to mice in each group, following the dosing scheme and results shown in Table 13.
  • the intravenous route of deuterium oxide show unexpected effect of extension the survival time of mice bearing human colon cancer HCT-116 cells.
  • the drinking of 30% deuterium oxide only extended 3 days for survival time, P>0.05.
  • the intravenous administration of deuterium oxide increased 10 days for survival time.
  • the drinking of 30% deuterium oxide in combination with 5-FU could extend 17 days for survival time, but the intravenous route of deuterium oxide in combination with 5-FU would increase 30 days for survival time ultimately, in a T/C 80.5%, P ⁇ 0.001.
  • Both intravenous route of deuterium oxide were significantly superior to the oral drinking of administration.
  • the intravenous route changes the pharmacodynamics of deuterium oxide and enhances the efficacy of it, also improves the survival time. Finally, it will be beneficial to patients with cancer therapy.
  • liver cancer H22 Ascites tumor in tumor-bearing mice by 42 ⁇ 1° C. hyperthermic intraperitoneal retention lavage using deuterium oxide in combination with cisplatin, and using deuterium oxide (42° C.) in combination with cisplatin.
  • Liver cancer H22 ascites tumor cell line was provided by NANJING KEYGEN BIOTECH. CO., LTD.
  • Test drugs cisplatin, and the Ringer's deuterium oxide solution as prepared in Example 6.
  • mice model was established 7 to 8 days after inoculation, and the mice were randomized with 18 animals/group.
  • Cisplatin were dissolved in a 42 ⁇ 1° C. Ringer's deuterium oxide solution, and used to lavage the peritoneal cavity of the tumor-bearing mice.
  • Blank control group normal Ringer's solution, 10 ml/kg, room temperature
  • Normal chemo group cisplatin 0.6 mg/kg+normal Ringer's solution, 10 ml/kg, room temperature
  • Room temperature low-dose deuterium oxide+cisplatin group (Ringer's deuterium oxide solution, 5 ml/kg+cisplatin 0.6 mg/kg)
  • Room temperature mid-dose deuterium oxide+cisplatin group (Ringer's deuterium oxide solution, 20 ml/kg+cisplatin 0.6 mg/kg); 5).
  • Room temperature high-dose deuterium oxide+cisplatin group (Ringer's deuterium oxide solution, 40 ml/kg+cisplatin 0.6 mg/kg); 6). Hyperthermic low-dose deuterium oxide+cisplatin group (42 ⁇ 1° C. Ringer's deuterium oxide solution, 5 ml/kg+cisplatin 0.6 mg/kg); 7). Hyperthermic mid-dose deuterium oxide+cisplatin group (42 ⁇ 1° C. Ringer's deuterium oxide solution, 20 ml/kg+cisplatin 0.6 mg/kg); 8). Hyperthermic high-dose deuterium oxide+cisplatin group (42 ⁇ 1° C. Ringer's deuterium oxide solution, 40 ml/kg+cisplatin 0.6 mg/kg);
  • mice The peritoneal cavity of mice was lavaged with the above compositions which were retained for 10 min in the peritoneal cavity after being introduced, which was repeated for 3 times. The lavage was performed once another day for 5 successive times. The body weight and abdomen circumference of mice were measured on each day before administration of the drugs, and the daily living status of mice was observed. 24 hours after the administration of drugs was completed (on day 11), 8 mice from each group were sacrificed, the volume of ascitic fluid was measured, and bodies of the mice were dissected to observe the peritoneal organs and metastasis to lung. The rest of mice were observed for their survival time, and the extension of life was calculated.
  • Cisplatin is a representative anti-tumor platinum preparation, and deuterium oxide has a broad-spectrum effect of enhancing anti-tumor efficacy.
  • the results demonstrate that the 42° C. hyperthermic intraperitoneal lavage with deuterium oxide in combination with cisplatin could significantly extend the survival time, inhibit production of ascitic fluid than deuterium oxide under room temperature in mice bearing H22 ascites tumors.
  • the application of hyperthermic deuterium oxide exhibits an unexpected anti-tumor effect of enhancing, thereby improves quality of life of the tumor-bearing mice.
  • sarcoma S 180 (ascites type) in tumor-bearing mice by 42 ⁇ 1° C. hyperthermic intraperitoneal retention lavage using deuterium oxide in combination with oxaliplatin and using deuterium oxide in combination with oxaliplatin and mitomycin.
  • sarcoma S 180 (ascites type) cell line was provided by NANJING KEYGEN BIOTECH. CO., LTD.
  • Test drugs oxaliplatin, mitomycin, and the glucose deuterium oxide solution as prepared in Example 2.
  • mice model was established 7 to 8 days after inoculation, and the mice were randomized with 12 animals/group.
  • Oxaliplatin and mitomycin were dissolved in a 42 ⁇ 1° C. glucose deuterium oxide solution, and used to lavage the peritoneal cavity of the tumor-bearing mice.
  • Blank control group (5% glucose injection, 5 ml/kg); 2). Chemo group (oxaliplatin 0.8 mg/kg+5% glucose injection, 5 ml/kg); 3). Low-dose deuterium oxide+oxaliplatin group (5% glucose deuterium oxide solution, 5 ml/kg+oxaliplatin 0.8 mg/kg); 4). Mid-dose deuterium oxide+oxaliplatin group (5% glucose deuterium oxide solution, 20 ml/kg+oxaliplatin 0.8 mg/kg); 5). High-dose deuterium oxide+oxaliplatin group (5% glucose deuterium oxide solution, 40 ml/kg+oxaliplatin 0.8 mg/kg); 6).
  • Low-dose deuterium oxide+oxaliplatin+mitomycin group (42 ⁇ 1° C. 5% glucose deuterium oxide solution, 5 ml/kg+oxaliplatin 0.8 mg/kg+mitomycin 0.4 mg/kg); 7). Mid-dose deuterium oxide+oxaliplatin+mitomycin group (42 ⁇ 1° C. 5% glucose deuterium oxide solution, 20 ml/kg+oxaliplatin 0.8 mg/kg+mitomycin 0.4 mg/kg); 8). High-dose deuterium oxide+oxaliplatin+mitomycin group (42 ⁇ 1° C. 5% glucose deuterium oxide solution, 40 ml/kg+oxaliplatin 0.8 mg/kg+mitomycin 0.4 mg/kg).
  • the peritoneal cavity was lavaged with the 42 ⁇ 1° C. glucose deuterium oxide solution in combination with the above composition, which were retained for 10 min in the peritoneal cavity after being introduced, which was repeated for 3 times.
  • the lavage was performed once another day for 5 successive times.
  • the body weight and abdomen circumference of mice were measured on each day before administration of the drugs, and the daily living status of mice was observed. 24 hours after the administration of drugs was completed (on day 11), 4 mice from each group were sacrificed, the volume of ascitic fluid was measured, and bodies of the mice were dissected to observe the peritoneal organs and metastasis to lung. The rest of mice were observed for their survival time, and the extension of life was calculated.
  • Oxaliplatin is a third-generation anti-tumor platinum preparation
  • mitomycin is an anti-tumor antibiotic to which tumor cells in G0 to S phases are sensitive
  • deuterium oxide has a broad-spectrum effect of enhancing anti-tumor efficacy, to which tumor cells in the S phase are also sensitive. Their combination can further enhance anti-tumor efficacy.
  • the results demonstrate that the hyperthermic deuterium oxide in combination with oxaliplatin and mitomycin can also significantly extend the survival time of mice bearing sarcoma S 180 , and inhibits production of ascitic fluid in mice bearing sarcoma S 180 . This indicates that combination of hyperthermic deuterium oxide with platinum preparation and anti-tumor antibiotics has general applicability in inhibition of growth of various tumors.
  • Test drugs 5-fluorouracil (5-FU), and the glucose (5%) deuterium oxide solution (containing 5 g glucose per 100 ml) prepared in Example 2.
  • Tumor cells were resuscitated and cultured according to a routine procedure, a suspension of cultured HCT-116 cells was collected, sterile sodium chloride physiological solution was added thereto to make a suspension at a concentration of 1 ⁇ 10 7 cells/ml, and 0.1 ml of the suspension was subcutaneously inoculated into the right axillary fossa of each nude mouse.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized with 8 mice per group. Meanwhile drugs were administered by injection into tail vein, once every three days, for 21 successive days. By measuring the tumor diameter, the anti-tumor efficacy of test samples was dynamically observed, and the body weight of animals was also recorded to observe the toxicity of the test samples. 21 days after administration, the nude mice were sacrificed, and tumors were harvested by surgery, weighed and photographed. Bone marrow nucleated cells were isolated by a routine method, DNA was extracted from the cells, the OD value was measured in a UV-260 spectrometer as a representative of the DNA content, and inhibition of DNA synthesis by the test samples was observed.
  • test used 7 groups in total, with 8 animals per group.
  • Negative control group 5% glucose injection, 10 ml/kg; 2) Paclitaxel positive control group: paclitaxel (8 mg/kg) diluted in sodium chloride physiological solution; 3) High-dose 5-FU positive control group: 5-FU (30 mg/kg) diluted in 5% glucose injection; 4) Low-dose 5-FU positive control group: 5-FU (12 mg/kg) diluted in 5% glucose injection. 5) Test group 1: 5-FU (12 mg/kg) diluted in the glucose deuterium oxide solution (5 ml/kg). 6) Test group 2: 5-FU (12 mg/kg) diluted in the glucose deuterium oxide solution (10 ml/kg). 7) Test group 3: 5-FU (12 mg/kg) diluted in the glucose deuterium oxide solution (20 ml/kg).
  • Tumor volume (TV) was calculated by the following equation:
  • a and b refer to length and width, respectively.
  • RTV relative tumor volume
  • V 0 is the tumor volume measured on initial administration (i.e. do)
  • V t is the tumor volume measured each time afterwards.
  • T RTV RTV of the treatment group
  • C RTV RTV of the negative control group.
  • ATW NCG Average tumor weight in negative control group
  • ATW DG Average tumor weight in drug-dosed group
  • Criteria of efficacy evaluation Inhibition of tumor growth ⁇ 40%, not efficacious; Inhibition of tumor growth ⁇ 40% and statistically P ⁇ 0.05, efficacious.
  • Anti-tumor activity evaluation by xenograft tumor volume the results demonstrate that deuterium oxide in combination with low-dose 5-FU showed a good inhibitory effect on the xenograft tumors; 21 days after administration, the tumor volumes were 1.22 ⁇ 0.15 cm 3 in the group receiving the deuterium oxide solution (5 ml/kg) in combination with 5-FU, 1.45 ⁇ 0.25 cm 3 in the group receiving the deuterium oxide solution (10 ml/kg) in combination with 5-FU, and 1.27 ⁇ 0.24 cm 3 in the group receiving the deuterium oxide solution (20 ml/kg) in combination with 5-FU, all with a T/C ⁇ 40% as compared to the negative control group, and satisfied the criteria for pharmacological efficacy.
  • Anti-tumor activity evaluation by xenograft tumor weight the results demonstrate that deuterium oxide in combination with low-dose 5-FU showed a good inhibitory effect on the xenograft tumors; 21 days after administration, the inhibitions were 56.32% in the group receiving the deuterium oxide solution (5 ml/kg) in combination with 5-FU, 53.70% in the group receiving the deuterium oxide solution (10 ml/kg) in combination with 5-FU, and 54.22% in the group receiving the deuterium oxide solution (20 ml/kg) in combination with 5-FU, all with a T/C>40% and P ⁇ 0.001 as compared to the tumor weight in the negative control group, and all satisfied the criteria for pharmacological efficacy.
  • Toxicity reduction importantly, in the high-dose paclitaxel and 5-FU positive control groups, despite apparent inhibition of tumor growth, the body weight of tumor-bearing mice dropped greatly from 18.4 ⁇ 0.5 g to 16.8 ⁇ 0.9 g and to 17.4 ⁇ 0.5 g, respectively, and the bone marrow DNA content also decreased, indicating significant toxicity of paclitaxel and 5-FU to animals.
  • the deuterium oxide solution in combination with 5-FU (10 mg/kg, one third of that of control) can achieve the same efficacy as high-dose paclitaxel and 5-FU (30 mg/kg) (equivalence), while the body weight of the tumor-bearing mice during dosing did not drop, and the bone marrow DNA content did not decrease, without the toxicity caused by high-dose paclitaxel and 5-FU.
  • toxicity of anti-tumor drugs is very harmful to patients and even unacceptable to some weak or aged patients, chemotherapeutic drugs having low toxic side effects and a strong killing effect are urgently needed in tumor treatment.
  • deuterium oxide in combination with low-dose 5-FU has a great advantage in clinical application, as shown in Table 18 and FIG. 7 .
  • Test drugs gemcitabine (GEM) and the sodium chloride deuterium oxide solution prepared in Example 1.
  • Tumor cells were resuscitated and cultured according to a routine procedure, suspension of cultured MCF-7 cells was collected, sterile sodium chloride physiological solution was added thereto to make a suspension at a concentration of 1 ⁇ 10 7 cells/ml, and 0.1 ml of the suspension was subcutaneously inoculated into the right axillary fossa of each nude mouse.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized with 8 mice per group. Meanwhile drugs were administered by injection into tail vein, once every three days, for 21 successive days. By measuring the tumor diameter, the anti-tumor efficacy of test samples was dynamically observed. Meanwhile the body weight of animals was also recorded to observe the toxicity of the test samples. 21 days after administration, the nude mice were sacrificed, and tumors were harvested by surgery, weighed and photographed. Bone marrow nucleated cells were isolated by a routine method, DNA was extracted from the cells, the OD value was measured in a UV-260 spectrometer as a representative of the DNA content, and inhibition of DNA synthesis by the test samples was observed.
  • test used 7 groups in total, with 8 animals per group.
  • test used 7 groups The test used 7 groups:
  • Negative control group sodium chloride physiological solution, 10 ml/kg; 2) Paclitaxel positive control group: paclitaxel diluted in sodium chloride physiological solution (8 mg/kg); 3) Gemcitabine positive control group: gemcitabine diluted in sodium chloride physiological solution (20 mg/kg); 4) Low-dose gemcitabine control group: gemcitabine diluted in sodium chloride physiological solution (10 mg/kg); 5) Test group 1: gemcitabine (10 mg/kg) diluted in the sodium chloride deuterium oxide solution (5 ml/kg). 6) Test group 2: gemcitabine (10 mg/kg) diluted in the sodium chloride deuterium oxide solution (10 ml/kg). 7) Test group 3: gemcitabine (10 ml/kg) diluted in the sodium chloride deuterium oxide solution (20 ml/kg). 3. Observation of indicators: the same as Example 21. 4. Statistics: the same as Example 21.
  • Anti-tumor activity evaluation by xenograft tumor volume the sodium chloride deuterium oxide solution in combination with gemcitabine 10 mg/kg showed a good inhibitory effect on the xenograft tumors; 21 days after administration, the tumor volumes were 1.949 ⁇ 0.491 cm 3 in the group receiving the deuterium oxide solution 5 ml/kg in combination with gemcitabine, 1.743 ⁇ 0.503 cm 3 in the group receiving the deuterium oxide solution 10 ml/kg in combination with gemcitabine, and 1.671 ⁇ 0.386 cm 3 in the group receiving the deuterium oxide solution 20 ml/kg in combination with gemcitabine, all with a T/C ⁇ 40% as compared to the negative control group, and satisfied the criteria for pharmacological efficacy.
  • the group receiving gemcitabine 10 mg/kg alone showed only a slightly reduced tumor volume of 2.757 ⁇ 0.342 cm 3 with a T/C of 60.39%, which was >40% and did not satisfy the criteria for pharmacological efficacy.
  • deuterium oxide significantly enhances the anti-tumor efficacy of gemcitabine, as shown in FIG. 8 .
  • Anti-tumor activity evaluation by xenograft tumor weight the deuterium oxide solution in combination with gemcitabine showed a good inhibitory effect on the xenograft tumors; 21 days after administration, the inhibitions were 48.82% in the group receiving the deuterium oxide solution 5 ml/kg in combination with gemcitabine, 57.78% in the group receiving the deuterium oxide solution 10 ml/kg in combination with gemcitabine, and 60.70% in the group receiving the deuterium oxide solution 20 ml/kg in combination with gemcitabine, all with a T/C>40% and P ⁇ 0.001 as compared to the negative control group, and all satisfied the criteria for pharmacological efficacy.
  • the group receiving gemcitabine 10 mg/kg alone showed only a slightly reduced tumor weight and an inhibition of 39.18%, which was less than 40% and did not satisfy the criteria for pharmacological efficacy. Therefore, deuterium oxide significantly enhances the anti-tumor efficacy of gemcitabine, as shown in Table 19 and FIG. 9 .
  • Toxicity reduction importantly, during the experiment, the average body weight of tumor-bearing mice in the negative control group increased by 3.3 g; in the paclitaxel and gemcitabine positive control groups, despite apparent reduction in tumor weight, the body weight of tumor-bearing mice only slightly increased, and the bone marrow DNA content also only slightly increased, indicating certain toxicity of paclitaxel and gemcitabine to animals.
  • the sodium chloride deuterium oxide solution in combination with low-dose gemcitabine (10 mg/kg, half of that of control) can achieve the same efficacy as high-dose paclitaxel (8 mg/kg) and high-dose gemcitabine (20 mg/kg) (equivalence), while the body weight of the tumor-bearing mice increased similarly to the negative control group, and the bone marrow DNA content also increased, without the toxicity caused by high-dose paclitaxel and gemcitabine.
  • Toxicity of anti-tumor drugs is very harmful to patients and even unacceptable to some weak or aged patients, and thus causes a serious problem to clinical anti-tumor chemotherapy.
  • deuterium oxide in combination with low-dose gemcitabine has a great advantage in clinical applications, as shown in Table 19 and FIG. 10 .
  • 5-FU and gemcitabine are antimetabolites among cytotoxic anti-tumor drugs. It can be also seen in Examples 19 and 20 that deuterium oxide in combination with antimetabolite anti-tumor drugs has general applicability for inhibition of growth of various tumors.
  • Test drugs gemcitabine (GEM) and the sodium chloride deuterium oxide solution prepared in Example 1.
  • Tumor cells were resuscitated and inoculated, and sterile sodium chloride physiological solution was added thereto to make a cell suspension which was subcutaneously inoculated into the upper right axillary fossa of animals. 5 ⁇ 10 6 tumor cells were inoculated into each animal.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized with 8 mice per group. Meanwhile drugs were administered by injection into tail vein, once every three days, for 21 successive days. By measuring the tumor diameter, the anti-tumor efficacy of test samples was dynamically observed. Meanwhile the body weight of animals was also recorded to observe the toxicity of the test samples. 21 days after administration, the nude mice were sacrificed, and tumors were harvested by surgery, weighed and photographed.
  • test used 7 groups The test used 7 groups:
  • Negative control group sodium chloride physiological solution, 10 ml/kg; 2) Paclitaxel positive control group: paclitaxel diluted in sodium chloride physiological solution (8 mg/kg); 3) Gemcitabine positive control group: gemcitabine diluted in sodium chloride physiological solution (20 mg/kg); 4) Low-dose gemcitabine control group: gemcitabine diluted in sodium chloride physiological solution (10 mg/kg); 5) Test group 1: gemcitabine (10 mg/kg) diluted in the sodium chloride deuterium oxide solution (5 ml/kg). 6) Test group 2: gemcitabine (10 mg/kg) diluted in the sodium chloride deuterium oxide solution (10 ml/kg). 7) Test group 3: gemcitabine (10 ml/kg) diluted in the sodium chloride deuterium oxide solution (20 ml/kg). 3. Observation of indicators: the same as Example 21. 4. Statistics: the same as Example 21.
  • Anti-tumor activity evaluations by xenograft tumor volume and weight demonstrate that, 21 days after administration, as compared to the sodium chloride physiological solution control group, the group receiving low-dose gemcitabine alone showed a reduced tumor weight to 2.23 ⁇ 0.2 g and an inhibition of 23.6%, which however did not satisfy the criteria for pharmacological efficacy.
  • the deuterium oxide solution in combination with gemcitabine all showed a good inhibitory effect on the xenograft tumors; the group receiving the deuterium oxide solution 5 ml/kg in combination with gemcitabine showed a tumor weight of 1.34 ⁇ 0.38 g and a tumor proliferation ratio of 54.22%, the group receiving the deuterium oxide solution 10 ml/kg in combination with gemcitabine showed a tumor weight of 1.35 ⁇ 0.34 g and a tumor proliferation ratio of 53.70%, and the group receiving the deuterium oxide solution 20 ml/kg in combination with gemcitabine showed a tumor weight of 1.28 ⁇ 0.46 g and a tumor proliferation ratio of 56.32%, all having P ⁇ 0.001 and satisfying the criteria for pharmacological efficacy, as shown in FIGS. 11 and 12 .
  • the body weight of tumor-bearing mice barely increased, indicating significant toxicity of paclitaxel and gemcitabine to animals.
  • Deuterium oxide in combination with low-dose gemcitabine can achieve the same efficacy as high-dose paclitaxel and gemcitabine, does not cause the corresponding toxicity, and results in an increased body weight of tumor-bearing mice during administration, as shown in Table 20 and FIG. 13 .
  • Test drugs paclitaxel and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • Tumor cells were resuscitated and inoculated, and sterile sodium chloride physiological solution was added thereto to make a cell suspension which was subcutaneously inoculated into the upper right axillary fossa of animals. 5 ⁇ 10 6 tumor cells were inoculated into each animal.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized. Meanwhile drugs were administered by injection into tail vein, once every three days, for 21 successive days. The body weight of animals was also recorded to observe the toxicity of the test samples. 21 days after administration, the nude mice were sacrificed, and tumors were harvested by surgery, and weighed.
  • test used 6 groups in total, with 5 animals per group.
  • Control group sodium chloride physiological solution, 10 ml/kg; 2) Paclitaxel positive control group: paclitaxel (8 mg/kg) diluted in sodium chloride physiological solution; 3) Sodium chloride deuterium oxide solution (10 ml/kg); 4) Test group 1: paclitaxel (8 mg/kg) diluted in the sodium chloride deuterium oxide solution (5 ml/kg); 5) Test group 2: paclitaxel (8 mg/kg) diluted in the sodium chloride deuterium oxide solution (10 ml/kg); 6) Test group 3: paclitaxel (8 mg/kg) diluted in the sodium chloride deuterium oxide solution (20 ml/kg). 3. Observation of indicators: the same as Example 21. 4. Statistics: the same as Example 21.
  • Paclitaxel is an important phytogenic anti-tumor drug, having various types of a similar mechanism of action, including paclitaxel, paclitaxel liposomes, paclitaxel albumin, and docetaxel.
  • the results demonstrate that, 21 days after administration, as compared to the control group, the groups receiving the deuterium oxide solution (10 ml/kg and 20 ml/kg) in combination with paclitaxel (8 mg/kg) showed a good inhibitory effect on xenograft tumors, with a significant reduction in tumor weight, while the tumor inhibition T/C was 54.9% on day 21 with P ⁇ 0.001.
  • the group receiving paclitaxel (8 mg/kg) alone showed a reduction, but did not satisfy the criteria of >40% for pharmacological efficacy.
  • the group receiving the deuterium oxide solution (5 ml/kg) in combination with paclitaxel (12 mg/kg) showed a reduction, but did not satisfy the criteria of >40% for pharmacological efficacy.
  • Deuterium oxide as a broad-spectrum anti-tumor efficacy-enhancing agent can also enhance the efficacy of phytogenic anti-tumor drugs.
  • Test drugs thiotepa and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • Tumor cells were resuscitated and inoculated, and sterile sodium chloride physiological solution was added thereto to make a cell suspension which was subcutaneously inoculated into the upper right axillary fossa of animals. 5 ⁇ 10 6 tumor cells were inoculated into each animal.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized. Meanwhile drugs were administered by injection into tail vein, once every three days, for 21 successive days. The body weight of animals was also recorded to observe the toxicity of the test samples. 21 days after administration, the nude mice were sacrificed, and tumors were harvested by surgery, and weighed.
  • the test used 5 groups in total, with 5 animals per group.
  • Control group sodium chloride physiological solution, 10 ml/kg; 2) Thiotepa positive control group: thiotepa (0.2 mg/kg) diluted in sodium chloride physiological solution; 3) Test group 1: thiotepa (0.2 mg/kg) diluted in the sodium chloride deuterium oxide solution (1 ml/kg); 4) Test group 2: thiotepa (0.2 mg/kg) diluted in the sodium chloride deuterium oxide solution (10 ml/kg); 5) Test group 3: thiotepa (0.2 mg/kg) diluted in the sodium chloride deuterium oxide solution (25 ml/kg). 3. Observation of indicators: the same as Example 21. 4. Statistics: the same as Example 21.
  • Thiotepa is an ethyleneimine alkylating agent involved in guanine binding and affecting DNA synthesis, and is effective on various types of tumor cells, especially bladder cancer cells.
  • Deuterium oxide in combination with thiotepa can synergistically enhance the effect of thiotepa against bladder cancer cells, increased the inhibition of cancer cell growth from 39% (when thiotepa is used alone) to 54%-63.4%, which verifies the function of deuterium oxide as a broad-spectrum anti-tumor efficacy-enhancing agent.
  • the dose of deuterium oxide is very low (1 ml/kg), the effect is not significant.
  • Test drugs bevacizumab (Avastin, Roche) and the sodium chloride deuterium oxide solution, prepared in Example 1.
  • Tumor cells were resuscitated and cultured according to a routine procedure, suspension of cultured PANC-1 cells was collected, sterile sodium chloride physiological solution was added thereto to make a suspension at a concentration of 1 ⁇ 10 7 cells/ml, and 0.1 ml of the suspension was subcutaneously inoculated into the right axillary fossa of each nude mouse.
  • the diameter of xenograft tumors in the nude mice was measured with a vernier caliper, and 10 days after inoculation, when tumors grew to 100 to 110 cm 3 , the animals were randomized. Meanwhile drugs were administered by injection into tail vein, once every three days, for 14 successive days. The body weight of animals was also recorded to observe the toxicity of the test samples. 14 days after administration, the dosing was discontinued for 1 week, then the nude mice were sacrificed, tumors were harvested by surgery and weighed, and the microvessel density (MVD) was examined.
  • MMD microvessel density
  • Tumors were stained by a standard EnVisionTM method, the number of microvessels was counted by the Weidner microvessel method, the entire field was observed under 100 ⁇ magnification, the areas having the highest microvessel density of the tumor were selected for counting, the microvessel density in three magnified fields was counted under 400 ⁇ magnification, and the obtained values of microvessel density were averaged as the MVD.
  • the test used 4 groups in total, with 5 animals per group.
  • bevacizumab is an angiogenesis inhibitor.
  • microvessels and blood supply are reduced.
  • deuterium oxide as a broad-spectrum anti-tumor efficacy-enhancing agent can also enhance the effect of bevacizumab in reducing the microvessel density (MVD) in tumor tissue, reducing the blood supply to pancreatic cancer PANC-1 cells, and in turn inhibiting tumor growth.
  • human colon cancer cell line HCT-116 was provided by NANJING KEYGEN BIOTECH. CO., LTD.
  • Modeling 0.2 ml suspension of HCT-116 cancer cells containing 1 ⁇ 10 7 cells/ml (2 ⁇ 10 6 cells in total) was inoculated into the peritoneal cavity of the nude mice.
  • Test drugs 5-FU, the 6% hydroxyethyl starch (200/0.5) deuterium oxide solution prepared in Example 10, and the 0.9% sodium chloride deuterium oxide solution, prepared in Example 1.
  • mice were established 7 to 8 days after inoculation into the nude mice, and the mice were randomized with 18 animals/group.
  • 5-FU was separately dissolved in the hydroxyethyl starch deuterium oxide solution at 42° C., and in the sodium chloride deuterium oxide solution at 42° C., for intraperitoneal lavage of tumor-bearing mice.
  • Blank control group (42° C. sodium chloride physiological solution, 10 ml/kg); 2). Normal chemo group (42° C. sodium chloride physiological solution, 10 ml/kg+ 5-FU 20 mg/kg); 3). Low-dose sodium chloride deuterium oxide solution+5-FU group (42° C. sodium chloride deuterium oxide solution 5 ml/kg+5-FU 20 mg/kg); 4). Mid-dose sodium chloride deuterium oxide solution+5-FU group (42° C. sodium chloride deuterium oxide solution 20 ml/kg+5-FU 20 mg/kg); 5). High-dose sodium chloride deuterium oxide solution.+5-FU group (42° C.
  • the peritoneal cavity of nude mice was lavaged with the above compositions which were retained for 20 min in the peritoneal cavity after being introduced, which was performed once a day for 5 successive times.
  • the body weight and abdomen circumference of the nude mice were measured on each day before administration of the drugs, and the daily living status of mice was observed.
  • 4 nude mice from each group were sacrificed, and bodies of the nude mice were dissected to observe the cancer cells and peritoneal organs. The rest of nude mice were observed for their survival time, and the extension of life was calculated.
  • Hydroxyethyl starch is a polymerexcipients for drugs, shows a long retention time in blood, and now has been a regular plasma replacement in clinical settings.
  • the results demonstrate that the 42° C. hyperthermic intraperitoneal lavage using a hydroxyethyl starch deuterium oxide solution in combination with 5-FU can significantly extend the survival time of nude mice bearing colon cancer cell and enhance the anti-tumor efficacy, apparently superior to the intraperitoneal lavage using a sodium chloride deuterium oxide solution in combination with 5-FU.
  • Test drugs gemcitabine, the HP- ⁇ -CD deuterium oxide solution prepared in Example 12, and the 0.9% sodium chloride deuterium oxide solution prepared in Example 2.
  • mice were established 7 to 8 days after inoculation into the nude mice, and the mice were randomized with 18 animals/group.
  • Gemcitabine was separately dissolved in the HP- ⁇ -CD deuterium oxide solution at 42° C., and in the sodium chloride deuterium oxide solution at 42° C., for intraperitoneal lavage of tumor-bearing mice.
  • Blank control group (42° C. sodium chloride physiological solution, 10 ml/kg); 2). Normal chemo group (42° C. sodium chloride physiological solution, 10 ml/kg+gemcitabine 20 mg/kg); 3). Low-dose sodium chloride deuterium oxide solution+gemcitabine group (42° C. sodium chloride deuterium oxide solution, 5 ml/kg+gemcitabine 20 mg/kg); 4). Mid-dose sodium chloride deuterium oxide solution+gemcitabine group (42° C. sodium chloride deuterium oxide solution, 20 ml/kg+gemcitabine 20 mg/kg); 5). High-dose sodium chloride deuterium oxide solution+gemcitabine group (42° C.
  • the peritoneal cavity of nude mice was lavaged with the above compositions which were retained for 20 min in the peritoneal cavity after being introduced, which was performed once a day for 5 successive times.
  • the body weight and abdomen circumference of the nude mice were measured on each day before administration of the drugs, and the daily living status of mice was observed.
  • 4 nude mice from each group were sacrificed, and bodies of the nude mice were dissected to observe the cancer cells and peritoneal organs. The rest of nude mice were observed for their survival time, and the extension of life was calculated.
  • ⁇ -cyclodextrin is a cyclic oligosaccharide and useful as a drug stabilizer.
  • HP- ⁇ -CD and sulfobutylether- ⁇ -cyclodextrin (SBE- ⁇ -CD) have similar properties, are both readily soluble in water, can also solubilize insoluble drugs, can control drug release, have good safety, and are suitable for preparation of lavage solutions and mucosa administrating systems.
  • the sodium chloride deuterium oxide solution as an anti-tumors drug carrier in which gemcitabine was dissolved showed an anti-tumor efficacy-enhancing effect.
  • deuterium oxide is a medium of small molecules, resides in the peritoneal cavity for only a short time, and is rapidly metabolized, lowering the anti-tumors effect of gemcitabine.
  • HP- ⁇ -CD shows a long retention time in blood, and slowly releases the gemcitabine dissolved therein. The results demonstrate that the 42° C.
  • hyperthermicintraperitoneal lavage using a HP- ⁇ -CD deuterium oxide solution in combination with gemcitabine can significantly extend the survival time of nude mice bearing pancreatic cancer cell and enhance the anti-tumor efficacy, superior to the intraperitoneal lavage using a sodium chloride deuterium oxide solution in combination with gemcitabine, and only requires a small dose which is readily acceptable to patients.
  • bladder cancer patients diagnosed with superficial bladder cancer (SBC) by cystoscopy and pathological examination and having undergone transurethral resection of bladder tumor (TURBt), were subjected to intrabladder perfusion and lavage for 60 min with a 50 ml 0.08% sodium hyaluronate deuterium oxide solution which had been warmed to 43.5 ⁇ 1° C. in a hyperthermic perfusion and lavage apparatus (BR-TRG-1 hyperthermic perfusion intraperitoneal treatment system, manufactured by Baorui Medical Technology Co., Ltd, Guangzhou, China) and mixed with mitomycin (MMC, 40 mg/50 ml).
  • SBC superficial bladder cancer
  • TURBt transurethral resection of bladder tumor
  • the anti-tumors drug mitomycin dissolved in only a sodium chloride solution When the anti-tumors drug mitomycin dissolved in only a sodium chloride solution is used for intrabladder perfusion and lavage to treat SBC, urine stimulates the inner cavity of bladder and often causes great pain to patients because the anti-tumors drug damages the glucosamine protection layer lining the epithelium of the bladder cavity, which results in hematuria and cease of the treatment. Furthermore, the anti-tumors drug mitomycin has a short life in a sodium chloride solution, which reduces its effect and leads to a tumor recurrence rate as high as 78% and eventually to a failure of treatment.
  • the sodium hyaluronate is a linear macromolecule and acid mucopolysaccharide, has excellent anti-inflammatory and anti-viscous performance, and can slow down drug release.
  • the sodium hyaluronate deuterium oxide solution is used for intrabladder perfusion, the sodium hyaluronate can temporarily play the role of the glucosamine protection layer lining the epithelium of the bladder and prolong the retention time of the anti-tumors drug mitomycin in bladder, while deuterium oxide also enhances the effect of mitomycin.
  • Their combination can not only enhance the efficacy of the anti-tumors drug, but also reduce the side effects of the anti-tumors drug.
  • Test sample the sodium chloride deuterium oxide solution (abundance 99.9%), prepared in Example 1.
  • Dosing scheme A maximum dosing method was used, in which the sodium chloride deuterium oxide solution prepared in Example 1 was intravenously injected at a dose of 20 ml/kg into 20 rats, half male and half female, at an injection speed of 2 ml/min. An equal volume of a 0.9% sodium chloride rejection was given to the control group containing 10 rats, half male and half female.
  • the animals showed a good general status and a normal increase in body weight.
  • Dosing scheme A method of repeatedly administrating the maximum dose was used, in which the sodium chloride deuterium oxide solution, prepared in Example 1 was intravenously injected once a day at a dose of 20 ml/kg and an injection speed of 2 ml/min to 20 rats, half male and half female, for 5 successive days. An equal volume of a 0.9% sodium chloride rejection was given to the control group containing 10 rats, half male and half female.
  • the animals showed a good general status and a normal increase in body weight.
  • the minimum lethal dose (MLD) of the sodium chloride deuterium oxide solution, as the test sample is greater than 20 ml/kg.

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CN114831931A (zh) 2022-08-02
CN114848589A (zh) 2022-08-05
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JP2017516854A (ja) 2017-06-22
US20190262267A1 (en) 2019-08-29
AU2015267897A1 (en) 2017-01-19
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US11090330B2 (en) 2021-08-17
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